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Editorial theme | Use of checkpoint inhibitors in AML therapy
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Acute myeloid leukemia (AML) is a hematological cancer characterized by uncontrolled growth of abnormal myeloblasts that infiltrate the bone marrow, blood, and other tissues.1 In 1973, for the first time, the induction regimen known as “7+3” (anthracycline + cytarabine) was reported, and for over four decades it has been the standard induction regimen for AML. However, since 2017, there has been an explosion of new treatment options, in particular therapeutic agents targeting specific subtypes of AML.2
Given the important role of the immune system in cancer eradication, immunotherapies such as vaccines, drug-conjugated and bispecific monoclonal antibodies, cell-based therapy, and immune checkpoint inhibitors are being evaluated.3 Here, we provide an overview of the use of checkpoint inhibitors in AML therapy — the next AML Hub editorial theme.
The use of immune checkpoint inhibitors, such as anti-PD-1, anti-PD-L1, or anti-CTLA-4, in combination with chemotherapy or hypomethylating agents (HMAs) is promising.4 At the 2018 American Society of Hematology Annual Meeting, Jacalyn Rosenblatt discussed the scientific rationale for incorporating checkpoint inhibitors in AML therapy, suggesting the following reasons for the use of checkpoint inhibitors at remission (see full article here):
- The observed increase of PD-L1 expression in the bone marrow (BM) of patients with TP53 mutations and patients with adverse cytogenetics, compared to healthy controls
- The apparent increase of TIM-3 (immune checkpoint molecule) expression on CD4 and CD8 T cells in the BM and high PD-1 in peripheral CD4+ T cells in patients achieving remission
At the 44th European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting, Arnon Nagler discussed the use of checkpoint inhibitors with the AML Hub (video below). His focus was nivolumab, a PD-1 inhibitor, for the prevention of posttransplantation relapse in patients with AML.
VIDEO INTERVIEW: Prof. Arnon Nagler | EBMT 2018 | Prospects of immune checkpoint inhibitors for prevention of SCT relapse in AML
Prospects of immune checkpoint inhibitors for prevention of SCT relapse in AML
There are several completed and ongoing clinical trials evaluating the benefit of immune checkpoint inhibitors, alone and in combination, in patients with AML.4 Results of clinical trials on immune checkpoint inhibitors as monotherapy are reported in Table 1.
Table 1. Clinical trials on immune checkpoint inhibitors as monotherapy
|
ALL, acute lymphoblastic leukemia; allo-SCT, allogeneic stem cell transplantation; AML, acute myeloid leukemia; CR, complete response; MDS, myelodysplastic syndrome; MoA, mechanism of action |
|||||
|
Investigational medication |
MoA |
N |
Phase |
Indication |
Results |
|---|---|---|---|---|---|
|
CT-011 |
Anti-PD-1 antibody |
17 |
I |
Hematologic cancer |
Only one of the eight AML patients responded after the first dose of CT-011, with a reduction in peripheral blasts (50% to 5%) |
|
Ipilimumab |
Anti-CTLA-4 antibody |
28 |
I |
Hematologic malignancies relapsed after allo-SCT |
CR observed in five patients (four with extramedullary AML and one with MDS developing into AML) treated with 10 mg per kilogram of body weight |
|
Ongoing clinical trials |
|||||
|
Pembrolizumab
|
Anti-PD-1 antibody |
|
I |
Refractory AML |
|
|
I |
Hematologic malignancies (including AML) relapsed after allo-SCT |
||||
|
I |
AML/MDS/ALL relapsed after allo-SCT |
||||
|
II |
AML post remission in patients ≥ 60 years transplant ineligible |
||||
|
Pembrolizumab + autologous SCT |
Anti-PD-1 antibody |
II |
AML with high risk of relapse ineligible for allo-SCT |
||
|
Nivolumab |
Anti-PD-1 antibody |
II |
AML in CR |
||
|
II |
AML in CR at high risk of relapse |
||||
Chemotherapeutic agents, such as anthracyclines, are inducers of immunogenic cell death, which leads to cytotoxic T lymphocyte (CTLs) proliferation and interferon-gamma (INF-γ) release. INF-γ release leads to PD-L1 increased expression on leukemic blasts. The increased expression of PD-L1 limits the ability of CTLs to eradicate leukemic blasts, resulting in resistant leukemia cells that may cause a relapse of the disease. The combination immune checkpoint inhibitors/chemotherapy could represent a good strategy to overcome this resistance and several clinical trials are testing it. Clinical trials on immune checkpoint inhibitors plus chemotherapy are reported in Table 2.
Table 2. Clinical trials on immune checkpoint inhibitors in combination with chemotherapy
|
AML, acute myeloid leukemia; CR, complete response; CRi, complete response with incomplete count recovery; MDS, myelodysplastic syndrome; R/R, relapsed/refractory |
||||
|
Investigational regimen |
N |
Phase |
Indication |
Results |
|---|---|---|---|---|
|
Nivolumab + cytarabine/ idarubicin |
32 |
II |
Upfront therapy AML, high-risk MDS
|
CR/CRi 72% |
|
High-dose cytarabine + pembrolizumab followed by pembrolizumab maintenance therapy in case of response |
13 |
II |
R/R AML |
CR/CRi 40% |
|
Ongoing clinical trials |
||||
|
Nivolumab + cyclophosphamide |
|
I/II |
R/R AML, high-risk MDS |
|
|
Pembrolizumab + high-dose cytarabine |
II |
R/R AML |
|
|
|
Nivolumab + cytarabine/ idarubicin |
44 |
I/II |
Frontline setting AML, high-risk MDS |
CR 64% (Read the study here) |
The combination of immune checkpoint inhibitors with HMAs has demonstrated good activity in preclinical studies and clinical trials are evaluating this combination in patients with AML (Table 3).
Table 3. Clinical trials on immune checkpoint inhibitors in combination with HMAs
|
AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; ORR, overall response rate; OS, overall survival; R/R, relapsed/refractory |
||||
|
Investigational regimen |
N |
Phase |
Indication |
Results |
|---|---|---|---|---|
|
Nivolumab + azacitidine |
70 |
II |
R/R AML |
ORR 33% Median OS 6.3 months (Study covered in the article here) |
|
Ongoing clinical trials |
||||
|
Ipilimumab + decitabine |
|
I |
R/R AML, R/R MDS |
|
|
Pembrolizumab + decitabine |
I/II |
R/R AML |
|
|
|
Pembrolizumab + azacitidine |
II |
R/R AML, R/R MDS, AML ≥ 65 years |
|
|
|
Nivolumab + azacitidine (arm I) Nivolumab + azacitidine + ipilimumab (arm II) |
II |
R/R AML, AML > 65 years |
|
|
|
Durvalumab + azactidine |
213 |
II |
High-risk MDS, AML ≥ 65 years |
(see below) |
At the 61st American Society of Hematology (ASH) meeting, the AML Hub spoke to Amer Zeidan, who discussed the results of an ongoing, randomized, study (NCT02775903) in patients (N = 213) with AML or high-risk MDS treated with AZA or AZA plus durvalumab, a PDL-1 inhibitor (video below). Even though the results showed no improvement in ORR, the study provided information on how immune checkpoint blockade plays a role in AML
VIDEO INTERVIEW: What is the role of immune checkpoint directed therapy in the treatment of AML?
What is the role of immune checkpoint directed therapy in the treatment of AML?
New specific immune checkpoint molecules, in addition to CTLA-4, PD-1, and PD-L1, have been identified. In an interview with the AML Hub, Naval Daver talked about unique AML and MDS checkpoint molecules, such as TIM-3, and ongoing clinical trials (video below). Several ongoing clinical trials are studying the combination of different immune checkpoint inhibitors and are reported in Table 4.
Table 4. Ongoing clinical trials on immunotherapy combinations
|
AML, acute myeloid leukemia; allo-SCT, allogeneic SCT; CR, complete response; MDS myelodysplastic syndrome; R/R relapsed/refractory; SCT, stem cell transplantation |
||
|
Investigational regimen |
Phase |
Indication |
|---|---|---|
|
Nivolumab + ipilimumab |
I |
Hematologic malignancies (including AML) relapsed after SCT |
|
Nivolumab (arm I); ipilimumab (arm II); nivolumab + ipilimumab (arm III) |
I |
AML after allo-SCT |
|
PDR001 (anti-PD-1) + decitabine (arm I); MBG453 (anti-TIM-3) + decitabine (arm II); PDR001 + MBG453 + decitabine (arm III); MBG453 (arm IV); PDR001 + MBG453 (arm V) |
I |
R/R AML, R/R MDS, AML ineligible for chemotherapy |
|
Pidilizumab (anti-PD-1) + dendritic cell vaccine |
II |
AML in CR |
Emerging immunotherapy modalities in AML and exciting data from ASH 2019
Conclusion4
Whilst the use of immune checkpoint inhibitors as monotherapy in AML seems ineffective, their combination with other treatments, such as chemotherapy or HMAs, is promising. Early results from studies evaluating these combinations in both the upfront setting and the R/R AML setting have demonstrated that the addition of immune checkpoint inhibitors to chemotherapy or HMAs is feasible and well-tolerated.
- Döhner H, Weisdorf DJ, Bloomfield CD, et al. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136-52. DOI: 1056/NEJMra1406184
- Lai C, Doucette K, Norsworthy K. Recent drug approvals for acute myeloid leukemia. J Hematol Oncol. 2019;12:100. DOI: 1186/s13045-019-0774-x
- Lichtenegger FS, Krupka C, Haubner S, et al. Recent developments in immunotherapy of acute myeloid leukemia. J Hematol Oncol. 2017;10:142. DOI: 1186/s13045-017-0505-0
- Stahl M & Goldberg AD. Immune checkpoint inhibitors in acute myeloid leukemia: Novel combinations and therapeutic targets. Curr Oncol Rep. 2019;21(4):37. DOI: 1007/s11912-019-0781-7
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